The focus of this work has been to understand the molecular details that control initial steps in the recognition of cells infected with pathogens such as viruses by cells of the innate and adaptive immune systems. In particular, we study the large family of major histocompatibility complex (MHC)-encoded molecules from a biophysical and structural perspective. Thus, we are interested in how MHC molecules, such as MHC-I and MHC-II molecules, interact with receptors on natural killer (NK) cells or on T lymphocytes through their NK and T cell receptors, respectively. These studies are dependent upon structural, functional, and biophysical analysis of the interaction of the molecules in question, and attempts are made to correlate binding properties with function and structure. Large DNA viruses of the herpesvirus family produce proteins that mimic host MHC-I molecules as part of their immunoevasive strategy, and we have directed effort to understand the function, cellular expression, and structure of a set of these MHC-I molecules encoded by the mouse cytomegalovirus (mCMV). We have analyzed the expression of several of these genes by transfection in different cell types, and have established that, unlike the classical MHC-I molecules, the viral MHC-I molecules (referred to as MHC-Iv) do not require either beta-2 microglobulin or self peptide for expression. In addition, MHC-Iv molecules m152 and m155 are not expressed at the cell surface under any circumstances. By engineering the m144 molecule for expression in E. coli, we produced X-ray diffraction quality crystals of m144 in complex with its beta-2 microglobulin light chain, and have completed data collection, molecular replacement solution, and refinement of the m144 structure at 1.9 Angstrom resolution. This study reveals, for the first time, that one of the mCMV MHC-Iv molecules indeed preserves the fundamental molecular fold characteristic of classical MHC-I molecules. The structure reveals a molecule that lacks bound peptide, and has unique structural features that contribute to thermal stability. Mutagenesis experiments confirm the importance of a unique disulfide bond of this molecule. In addition, we have examined the cellular expression of additional cytomegalovirus MHC-Iv immunoevasins, M37, m151, and m153. Each of these has unique cell biological features. In collaboration with Stipan Jonjic, University of Rijeka, we have generated monoclonal antibodies to m153, and have recently demonstrated that m153 forms stable non-covalent homodimers. Diffraction quality crystals of selenomethionyl m153, expressed in Drosophila S2 cells, have been obtained. Using single anomalous dispersion (SAD) methodology, we have solved the structure of m153, and refinement of the structure to 2.4 Angstrom resolution is underway. Efforts to express m145, m151, m152, and m155 are being explored.